10,5-(iminomethano)-10,11-dihydro-5h-dibenzo(a,d)cyclohepten-11-ones



United States Patent ABSTRACT OF THE DISCLOSURE 10,5-(imin0methano)10,11-dihydro 5H dibenzo[a,d] cycloheptene 11 ones having CNS and anti-bacterial properties are disclosed.

This invention relates to novel chemical compounds having useful biological properties. In particular, this invention relates to novel 10,5-(iminomethano)-10,11- dihydro-SH-dibenzo[a,d]cycloheptene 11 ones of the following generic Formula I:

wherein R represents hydrogen, or an organic group, such as, for example, a lower alkyl group containing from 1-6 carbon atoms, or an aralkyl group containing from 7-10 carbon atoms, such as, for example, the benzyl, phenethyl, or trimethoxybenzyl groups.

This invention also relates to the salts of the compounds of Formula I with pharmaceutically acceptable acids.

The compounds of Formula I are prepared from the corresponding lO,5-(iminomethano)-10,1l-dihydro 5H- dibenzo[a,d]-cycloheptene- 11,13 -dione of Formula II, wh erein R is as defined above, by reducing the 13-carbanyl function with a complex alkali metal aluminium hydride after protecting the ll-carbonyl function by converting it to a ketal function. Finally, the ketal function is removed to give the corresponding compound of Formula I wherein R is as defined above.

More specifically, a mixture of a 10,5-(imin0methano)- 10,11 dihydro 5H dibenzo[a,d]cyclohepten 11,13- dione of Formula II wherein R is as defined above, a water immiscible inert solvent such as, for example, benzene or tuluene, a molar excess of a lower alkanol or a lower alkylene glycol such as, for example, ethylene glycol or propylene glycol, and an acidic catalyst such as, for example, sulphuric acid or p-toluenesulphonic acid, is boiled in an apparatus suitable for the continuous removal of water until no more Water appears in the distillate. The mixture is cooled and then washed with an aqueous solution of an alkali metal hydroxide, preferably 1 N sodium hydroxide. The organic phase is evaporated and the residual ll-ketal of Formula III is used without Patented July 29, 1969 further purification. In its turn, this compound is dissolved in an inert solvent such as, for example, ether or tetrahydrofuran or dioxan and treated with a complex alkali metal aluminium hydride such as, for example, lithium aluminium hydride. The mixture is heated at a temperature within the range of from 30-100 C. for a period of time of up to one day to give, after hydrolysis of the resulting complex the crude ll-ketal of Formula IV. This compound, in its turn, is treated with an aqueous solution of a mineral acid for a period of time of up to one day. The mixture is rendered alkaline to give, after purification in a conventional manner, such as, for example, by chromatography or crystallization, the 10,5- (iminomethano)- 10,11 dihydro-SH-dibeno [a,d,]cyclohepten-l l-one of Formula I.

The latter compounds of Formula I may then be reacted with a pharmaceutically acceptable acid, such as, for example, hydrochloric, sulphuric, oxalic, maleic, or citric acid, to yield the corresponding acid addition salts which are pharmacologically equivalent to their free bases.

The compounds of Formula I possess anti-bacterial properties against gram-positive and gram-negative or ganisms. Thus they may be formulated in the form of lotions or creams containing from 0.1 to 1% of the active ingredient to be applied topically to the skin once to four times daily.

The compounds of this invention also possess marked activity upon the central nervous system, in particular anti-convulsant activity, especially against electro-shock to a very high degree, together with a low order of toxicity. Thus the compounds are useful as anti-convulsant agents. As such they may be formulated into tablets or capsules with suitable excipients such as, for example, starch or lactose, each tablet or capsule containing from -500 mg. of the active ingredient. Such capsules may be administered from one to four times per day for prolonged periods of time.

The starting materials for the compounds of this invention, that is the 10,5 (iminomethano) 10,11 dihydro 5H dibenzo[a,d]cycloheptene 11,13 diones of Formula II wherein R is as defined above are prepared as described in my co-pending U.S. patent application S.N. 552,387, filed May 24, 1966.

In brief, this process entails the addition of one molar proportion of bromine to SH-dibenzo[a,d]cycloheptene- S-carboxamide and treatment of the resulting product with boiling water or a boiling lower alkanol to give 11- bromo 10,5 (epoxymethano) 10,11 dihydro 5H- dibenzo[a,d]cycloheptene-13-one. In its turn, this compound is treated with either ammonium hydroxide or an aqueous solution of suspension of a primary amine of formula RNH wherein R is as defined above in a sealed vessel at a temperature in the range of to C. to give the corresponding 11 hydroxy 10,5 (iminomethano)- 10,11 dihydro 5H dibenzo[a,d]cycloheptene-13-one of Formula V wherein R is as defined above. In its turn thiscompoundisdissolvedorsuspended in an inert solvent, preferably acetone and treated with a molar excess of an aqueous solution of chromic acid to give the corresponding 10,5-(iminomethano)-10,11- dihydro 5H dibenzo[a,d]cycloheptene 11,13 dione of Formula II wherein R is as defined above.

The following formulae and examples are illustrative of this invention:

o=c u-a a e N a We III,

s c a EXAMPLE 1 The ethylene ketal of 10,5-(iminomethano)-10,11- dihydro-SH-dibenzo [a,d] cycloheptene- 1 1, 13-dione mixture is kept at room temperature overnight. The precipitate is collected and washed with water to give the hydrochloric acid addition salt of the title product with M.P. 284 C. (decomp.). The filtrate is rendered alkaline and extracted with ether. Evaporation of the ethereal extracts leaves the title product as an oil characterized by its infra-red absorption spectrum with a at 3340, 1673, 1600, 1497, and 1452 cmr EXAMPLE 3 In the same manner as described in Examples 1 and 2, but using as starting material 12-methyl-, 12-ethyl-, l2- propyl-, 12-butyl-, 12-pentyl-, 12-hexyl-, 12-benzyl-, 12- phenethyl-, or 12-trimetl1oxybenzyl-10,5-(iminomethano)- 10,1 1 dihydro-SH-dibenzo [a,d] cycloheptene-l 1,13-dione instead of 10,5-(iminomethano)-l0,11-dihydro-5H-dibenzo [a,d] cycloheptene-l 1,13-dione the corresponding l2-methyl-, 12-ethyl-, 12-propyl-, 12-butyl-, 12-pentyl-, l2-hexyl, "12-benzyl-, 12-phenethy1-, or IZ-trimethoxybenzyl 10,5 (iminomethano)-l0,1l-dihydro-SH-dibenzo [a,d]cyclohepten-11-one is obtained.

The acid addition salts of the above compounds with mineral acids, such as, for example, hydrochloric or sulanolic solutions with the appropriate acid, to obtain the A mixture of 10.5-(iminoimethano)-5H-dibenzo [a,d]-

cycloheptene-11,13-dione (10 g.) benzene (200 ml.), ethylene glycol (10 ml.), p-toluenesulphonic acid (0.3 g.) is heated under reflux for 20 hours, with continuous removal of water using a Dean-Stark head. The resulting suspension is cooled and diluted with aqueous sodium hydroxide solution (50 ml. of a 10% solution). The mixture is filtered and the solids are thoroughly washed with water and dried to give the title product with M.P. 265- 269 C. A further quantity of the product is obtained upon evaporation of the washed and dried organic phase.

EXAMPLE 2 10,5- (imonomethano) -10,1 l-dihydro-SH-dibenzo [a,d] cyclohepten- 1 l-one A suspension of the ketal obtained as described in Example 1 (5.0 g.), and lithium aluminum hydride (2.5 g.), in dry tetrahydrofuran (100 ml.), is stirred and heated under reflux for 5 hours. Water (6.0 ml.), is cautiously added to the cooled mixture and when the hydrolysis is complete the mixture is filtered through a pad of diatomaceous earth. The filtrate is combined with the washings of the inorganic precipitate and evaporated to dryness in vacuo. The oily residue thus obtained consists of oxalate, maleate, or citrate salts.

We claim:

1. A compound selected from the group which consists of compounds of the formula wherein R is selected from the group which consists of hydrogen, lower alkyl, benzyl, phenethyl and trirnethoxybenzyl; and addition salts thereof with pharmaceutically acceptable acids.

2. 10,5 (iminomethano) 10,11-dihydro-5H-dibenzo [a,d]cyclohepten-1l-one, as claimed in claim 1.

3. The hydrochloric acid addition salt of 10,5-(iminomethano) 10,1l-dihydro-SH-dibenzo[a,dJcycloheptenll-one, as claimed in claim 1.

4. The ethylene ketal of 10,5-(iminomethano)-10,11-

dihydro-SH-dibenzo [a,d] cycloheptene-l 1, 13-dione.

I V Us. (:1. X.R. gee-239.3, 289; 424-253 

